Although the cerebral cortex is responsible for all the intellectual life that makes us human, we know remarkably little about how this amazing structure is formed. We do know, however, that genetic conditions in which the cortex is not formed properly have devastating consequences. Neurological disorders, such as intractable pediatric epilepsy, are frequently associated with developmental brain malformations. Progress toward understanding the pathologic basis of these diseases has so far come from research on animal models of cortical malformation and from molecular genetic approaches to human neuronal migration disorders. Lissencephaly and Periventricular Heterotopia are such human neuronal migration disorders in which mutations in LIS1 and FLN1 genes result in severe defects in cortical neuronal migration. Both LIS1 and FLN1 have been suggested to regulate cytoskeleton and both interact with other key components in the neuronal migration signaling pathways. We have identified many LIS1 and FLN1 interacting proteins. One of the LIS1 interacting proteins, mNudE, was suggested to be essential for LIS1's function in microtubule regulation and neuronal migration. The overall goal of this research proposal is aimed at understanding the molecular mechanism of neuronal migration mediated by LISI-mNudE interaction and by FLN1. Specific aim 1 is to investigate the molecular mechanism and biological significance of mNudE and LIS1-mNudE interaction in cortical development, while specific aim 2 is to study the function of FLN1 and FLN1 mediated signal transduction in cortical development. Experimental approaches are focused on establishing mouse models to address the specific aims. Results from proposed experiments will bridge our knowledge from molecular mechanism of cortical neuronal migration to the formation of human brain, and will also provide important insight into the pathogenesis of human neurogenetic disorders. The candidate had a background in medicine and biomedical science, and has had intensive training in molecular approaches during Ph.D. and postdoctoral training. She now seeks further training in mouse genetics and neuroanatomy under the mentorship of Drs. Chris Walsh and David Kwaitkowski. These training will greatly enhance the candidate's potential in conducting independent scientific research. [unreadable] [unreadable]